Abstract 12306: Novel Role for the Lymphatic Microvasculature in Cardiac Stem Cell Trafficking in the Infarcted Myocardium
Lymphatic microvessels (LMVs) are characterized by discontinuous basal lamina, fenestrations, and lack of pericyte and smooth muscle cell lining, which are favorable features for cell diapedesis. Trafficking of immune and cancer cells via LMVs has clearly been documented; however, the role of LMVs in the migration of cardiac stem cells (CSCs) has never been established. In our study, developing LMVs were recognized by the expression of podoplanin while mature LMVs were identified by the presence of Lyve-1. In the intact mouse heart, LMVs were predominantly located in the epimyocardium. Shortly after myocardial infarction (MI), extensive remodeling of pre-existing LMVs and neolymphangiogenesis were observed. Activated podoplanin-positive LMVs were first identified in the border zone (BZ) 16 hours after coronary artery ligation. At 2 days, the number and size of LMVs in the BZ and necrotic area were markedly elevated. With the resolution of the inflammatory response at 14 days, loss of podoplanin labeling and appearance of Lyve-1-positive maturing LMVs was documented in the BZ and in the scar. Transgenic mice expressing GFP under the c-kit promoter were employed to monitor CSC migration over time. CSC mobilization towards the BZ was detected as early as 16 hours after MI. Concomitantly with the increase in LMV growth at 2 days post MI, accumulation of CSCs was observed in the BZ. CSCs were located in the vicinity of the newly-formed podoplanin-positive LMVs and traversed the endothelial lining of these vessels. Ex vivo, human CSCs adhered avidly to human Lyve-1-positive lymphatic endothelial cells (LECs). The efficiency of this interaction was similar to that detected between CSCs and HUVECs. However, the frequency of CSC transmigration through a monolayer of LECs was significantly higher with respect to HUVECs. To mimic the in vivo condition, we developed a tubulogenesis assays in three-dimensional matrix. By live cell imaging, we established that human CSCs actively intravasated into the lumen of the tubes formed by human LECs but not into the structures produced by HUVECs. Our findings document for the first time that CSCs interact in vivo and in vitro with LECs and strongly suggest that CSCs migrate through the lymphatic vessel wall in the infarcted heart.
- © 2013 by American Heart Association, Inc.